GPD2, also known as glycerol-3-phosphate dehydrogenase 2, is a key component of the glycerol phosphate shuttle. It plays a crucial role in regulating glucose oxidation. By boosting glucose oxidation, it provides fuel for the production of acetyl coenzyme A, which is involved in histone acetylation and the induction of genes encoding inflammatory mediators [1]. GPD2 also has implications in maintaining the balance between beneficial and detrimental effects of the inflammatory response during macrophage activation [1].

Knockdown of GPD2 in human hepatocarcinoma-derived HuH-7 cells and human neuroblastoma-derived SH-SY5Y cells lowered cancer stemness, suggesting its role in maintaining cancer stem cells [2]. In cancer, GPD2 knockout (KO) led to cell growth suppression and inhibition of tumor progression in vivo, independent of its conventional bioenergetic function. Instead, it was associated with changes in ether lipid metabolism, and the GPD2-ether lipid-Akt axis was described for cancer growth control [3]. In cervical cancer, lactate secreted by cancer cells upregulated GPD2 via histone lactylation, promoting M2 macrophage polarization [4]. In the heart, GPD2 deficiency exacerbated cardiac dysfunction after acute myocardial infarction, indicating its role in preventing myocardial ischemia-related damage [5]. In kidney cancer, knocking down GPD2 upregulated cytosolic GPD and promoted cancer cell proliferation by increasing glycerol-3-phosphate supply [6].

In conclusion, GPD2 is essential in multiple biological processes. Its role in macrophage-mediated inflammatory responses, cancer stemness maintenance, cancer progression, and cardiac function during ischemia has been revealed through functional studies including gene knockout models. These findings suggest GPD2 could be a potential target for treating inflammatory diseases and cancers, as well as for preventing cardiac damage during ischemia.